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(Circulation. 2008;118:363-372.)
© 2008 American Heart Association, Inc.

Heart Failure

Mast Cells Play a Critical Role in the Pathogenesis of Viral Myocarditis

Hirokazu Higuchi, MD; Masatake Hara, MD, PhD; Kanjo Yamamoto, MD, PhD; Tadashi Miyamoto, MD, PhD; Makoto Kinoshita, MD, PhD; Tasuku Yamada, MD; Koji Uchiyama, MD; Akira Matsumori, MD, PhD

From the Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto (H.H., A.M.); Cardiovascular Division, Otsu Red-Cross Hospital, Shiga (H.H., M.H.); Cardiovascular Division, Wakayama Red-Cross Hospital, Wakayama (K.Y., T.Y.); Cardiovascular Division, Hyogo Prefectural Amagasaki Hospital, Hyogo (T.M.); Kobe City Medical Center General Hospital, Hyogo (M.K.); and Cardiovascular Division, Osaka Red-Cross Hospital, Osaka (K.U.), Japan.

Correspondence to Akira Matsumori, MD, PhD, Department of Cardiovascular Medicine, Kyoto University, 54 Kawaracho Shogoin, Sakyo-ku, Kyoto 606-8397, Japan. E-mail amat{at}kuhp.kyoto-u.ac.jp

Received September 20, 2007; accepted May 23, 2008.

Background— Mast cells are powerful producers of multiple cytokines and chemical mediators playing a pivotal role in the pathogenesis of various cardiovascular diseases. We examined the role of mast cells in murine models of heart failure due to viral myocarditis, using 2 strains of mast cell–deficient mice.

Methods and Results— Two strains of mast cell–deficient mice, WBB6F1-Kit^W/Kit^W-v (W/W^V) and WCB6F1-Kitl^Sl/Kitl^Sl-d (Sl/Sl^d), were inoculated with 10 plaque-forming units of the encephalomyocarditis virus intraperitoneally. On day 14 after inoculation, survival of W/W^V mice was significantly higher than that of their control littermates (77% versus 31%; P=0.03; n=13). On histological examination on day 7, myocardial necrosis and cellular infiltration were significantly less pronounced in W/W^V and Sl/Sl^d mice than in their control littermates (area of infiltration, 7.6±3.5% versus 29.3±15.6%; P=0.002; area of necrosis, 7.6±3.5% versus 30.0±17.2%; P=0.003; n=10). Histological examination showed more severe changes in mast cell–reconstituted than in –nonreconstituted W/W^V and Sl/Sl^d mice. The gene expressions of mast cell proteases were upregulated in the acute phase of viral myocarditis and rose further in the subacute phase of heart failure. Their activation coincided with the development of myocardial necrosis and fibrosis and correlated with the upregulation of gene expression of matrix metalloproteinase-9. The histamine H1-receptor antagonist bepotastine improved encephalomyocarditis viral myocarditis.

Conclusions— These observations suggest that mast cells participate in the acute inflammatory reaction and the onset of ventricular remodeling associated with acute viral myocarditis and that the inhibition of their function may be therapeutic in this disease.

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